Critical Role of Donor Tissue Expression of Programmed Death Ligand-1 in Regulating Cardiac Allograft Rejection and Vasculopathy

Allograft vasculopathy is a major limiting factor in the long-term success of cardiac transplantation. T cells play a critical role in initiation of cardiac allograft rejection and allograft vasculopathy. The negative T-cell costimulatory pathway PD-1:PDL1/PDL2 (programmed death-1:programmed death l...

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Published in:	Circulation (New York, N.Y.) Vol. 117; no. 5; pp. 660 - 669
Main Authors:	JUN YANG, POPOOLA, Joyce, SHIN, Tahiro, YAGITA, Hideo, AZUMA, Miyuki, SAYEGH, Mohamed H, CHANDRAKER, Anil, KHANDWALA, Shakila, VADIVEL, Nidyanandh, VANGURI, Vijay, XUELI YUAN, DADA, Shirine, GULERIA, Indira, TIAN, Chaorui, JAVEED ANSARI, M
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott Williams & Wilkins 05-02-2008
Subjects:	Animals Antigens, Surface - genetics Apoptosis Regulatory Proteins - deficiency Apoptosis Regulatory Proteins - genetics Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Cardiovascular system CD4-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - immunology Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Gene Expression Regulation Graft Rejection - genetics Heart Transplantation - immunology Heart Transplantation - pathology Histocompatibility Antigens Class II - immunology Histocompatibility Testing Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Pharmacology. Drug treatments Programmed Cell Death 1 Receptor Tissue Donors Transplantation, Homologous Vasodilator agents. Cerebral vasodilators Suboptimal donor Vascular disease Rejection Graft(material) Immunology lymphocytes transplantation Cardiovascular disease Homotransplantation Lymphocyte
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Summary:	Allograft vasculopathy is a major limiting factor in the long-term success of cardiac transplantation. T cells play a critical role in initiation of cardiac allograft rejection and allograft vasculopathy. The negative T-cell costimulatory pathway PD-1:PDL1/PDL2 (programmed death-1:programmed death ligand-1/2) plays an important role in regulating alloimmune responses. We investigated the role of recipient versus donor PD-1 ligands in the pathogenesis of allograft rejection with emphasis on the role of tissue expression in regulating this alloimmune response in vivo. We used established major histocompatibility complex class II- and class I-mismatched models of vascularized cardiac allograft rejection, blocking anti-PDL1 and anti-PDL2 antibodies, and PDL1- and PDL2-deficient mice (as donors or recipients) to study the role of the PD-1:PDL1/PDL2 pathway in chronic rejection. We also used PDL1-deficient and wild-type mice and bone marrow transplantation to generate chimeric animals that express PDL1 exclusively on either hematopoietic or parenchymal cells. PDL1 but not PDL2 blockade significantly accelerated cardiac allograft rejection in the bm12-into-B6 and B6-into-bm12 models. Although wild-type cardiac allografts survived long term, PDL1-/- donor hearts transplanted into wild-type bm12 mice exhibited accelerated rejection and vasculopathy associated with enhanced recipient T-cell alloreactivity. Interestingly, PDL1-/- recipients did not exhibit an accelerated tempo of cardiac allograft rejection. Using chimeric animals as donors, we show that PDL1 expression on cardiac tissue alone significantly prolonged graft survival compared with full PDL1-/- donor grafts in transplanted wild-type recipients. This is the first report to demonstrate that expression of the negative costimulatory molecule PDL1 on donor cardiac tissue regulates recipient alloimmune responses, allograft rejection, and vasculopathy.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0009-7322 1524-4539
DOI:	10.1161/circulationaha.107.741025